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We studied the effects of clarithromycin (CAM) and AZM on proinflammatory cytokine production from normal human bronchial epithelial (NHBE) cells. CAM decreased IL-8 over the first 6 h and then significantly increased interleukin (IL)-8 at 12\u201372 h after exposure ( P &lt; 0.0001). AZM also increased IL-8 at 24 and 48 h, and CAM increased granulocyte-macrophage colony-stimulating factor at 48 h. In the presence of LPS, both CAM and AZM dose-dependently increased IL-8 secretion over 24 h, but after 5 days of exposure to 10 \u03bcg\/ml CAM there is suppression of IL-8 ( P &lt; 0.001). PD-98059, an inhibitor of MAP kinase\/ERK kinase, inhibited CAM-induced IL-8 ( P &lt; 0.0001) and GM-CSF ( P &lt; 0.01) release. The p38 MAP kinase inhibitor SB-203580 increased CAM-induced IL-8 release ( P &lt; 0.001), and the c-jun NH<jats:sub>2<\/jats:sub>-terminal kinase inhibitor SP-600125 had no effect on IL-8. At 120 min and 6 h, CAM increased phospho-ERK1\/2 (pERK) but not phospho-p38 or phospho-JNK. Over the first 90 min, CAM at 10 \u03bcg\/ml inhibited pERK and then increased pERK in parallel with measured IL-8 secretion. After daily CAM exposure for 5 days, both IL-8 and pERK returned to baseline. The p38 MAP kinase inhibitor, SB-203580 increased ERK phosphorylation and IL-8 secretion. These results suggest that macrolide antibiotics can differentially modulate proinflammatory cytokine secretion in NHBE cells, in part through ERK.<\/jats:p>","DOI":"10.1152\/ajplung.00093.2005","type":"journal-article","created":{"date-parts":[[2005,8,6]],"date-time":"2005-08-06T00:31:12Z","timestamp":1123288272000},"page":"L75-L85","source":"Crossref","is-referenced-by-count":126,"title":["Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells"],"prefix":"10.1152","volume":"290","author":[{"given":"Masaharu","family":"Shinkai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory H.","family":"Foster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce K.","family":"Rubin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.22.1.3400"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0303104"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1210\/endo.143.2.8648"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.46.27489"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkh519"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/14.1.41"},{"key":"R7","doi-asserted-by":"crossref","unstructured":"Aoki Yand Kao PN.Erythromycin inhibits transcriptional activation of NF-kappaB, but not NFAT, through calcineurin-independent signaling in T cells.Antimicrob Agents Chemother43: 2678\u20132684, 1999.","DOI":"10.1128\/AAC.43.11.2678"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.4.872"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.35.10.2016"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251194298"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.152.6.8520783"},{"key":"R12","doi-asserted-by":"crossref","unstructured":"Carter ABand Hunninghake GW.A constitutive active MEK \u2013ERK pathway negatively regulates NF-kappa B-dependent gene expression by modulating TATA-binding protein phosphorylation.J Biol Chem275: 27858\u201327864, 2000.","DOI":"10.1074\/jbc.M003599200"},{"key":"R13","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.8.5219"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.01.00229701"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(95)00357-F"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(02)02042-3"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.5.1581-1585.2004"},{"key":"R18","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.1917"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1023\/A:1010975124110"},{"key":"R20","unstructured":"Fumimori T, Honda S, Migita K, Hamada M, Yoshimuta T, Honda J, Fukuda T, Suzuki R, Gotoh M, Eguchi K, and Aizawa H.Erythromycin suppresses the expression of cyclooxygenase-2 in rheumatoid synovial cells.J Rheumatol31: 436\u2013441, 2004."},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205348"},{"key":"R22","doi-asserted-by":"crossref","unstructured":"Hoffmann E, Dittrich-Breiholz O, Holtmann H, and Kracht M.Multiple control of interleukin-8 gene expression.J Leukoc Biol72: 847\u2013855, 2002.","DOI":"10.1189\/jlb.72.5.847"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307521200"},{"key":"R24","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072682"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00216.2002"},{"key":"R26","doi-asserted-by":"crossref","unstructured":"Kawasaki S, Takizawa H, Ohtoshi T, Takeuchi N, Kohyama T, Nakamura H, Kasama T, Kobayashi K, Nakahara K, Morita Y, and Yamamoto K.Roxithromycin inhibits cytokine production by and neutrophil attachment to human bronchial epithelial cells in vitro.Antimicrob Agents Chemother42: 1499\u20131502, 1998.","DOI":"10.1128\/AAC.42.6.1499"},{"key":"R27","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkf008"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1159\/000138716"},{"key":"R29","doi-asserted-by":"crossref","unstructured":"Kohyama T, Takizawa H, Kawasaki S, Akiyama N, Sato M, and Ito K.Fourteen-member macrolides inhibit interleukin-8 release by human eosinophils from atopic donors.Antimicrob Agents Chemother43: 907\u2013911, 1999.","DOI":"10.1128\/AAC.43.4.907"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1016\/0024-3205(92)90003-8"},{"key":"R31","unstructured":"Labro MT.Cellular accumulation of macrolide antibiotics. 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